Neuronal Pain Pathway Modulators
AssigneeThe Trustees of Columbia University in the City of New York
InventorsRichard Ambron, Ying-Ju Sung, Jeremy Greenwood, Leah Frye, Shi-Xian Deng, Yuli Xie, Donald W. Landry
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Abstract
The present invention relates to compounds that may be used to inhibit activation of protein kinase G (“PKG”). It is based, at least in part, on the discovery of the tertiary structure of PKG and the identification of molecules that either bind to the active site of PKG and/or are analogs of balanol.
Claims34
A pharmaceutical composition for treating chronic pain in a subject comprising a compound, in an amount effective at inhibiting long-term hyperexcitability of sensory neurons in a subject to which it is administered, represented by the following structure:
- where R1 and R2 are respectively H, (C1-C4)alkyl, (C2-C4)alkenyl, (C1-C4)alkoxy, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl or hydroxyl;
- R3 and R4 are respectively H, (C1-C4)alkyl, keto, (C2-C4)alkenyl, (C1-C4)alkoxy, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl or hydroxyl;
- R5 may be amido, (C1-C4)alkylamido, amido(C1-C4)alkyl;
- carbonyl(C1-C4)alkylamido;
- (C1-C4)alkylcarboxy(C1-C4)alkylamido, or amido(C1-C4)alkylamido;
- and
- R6 is hydroxy (C1-C4)alkylphenyl or a (C5-C13)cyclic or substituted or unsubstituted heterocyclic ring,
- wherein if R4 is keto, x is a single bond, and if R4 is not keto, x is a double bond;
- and m and n are respectively 0-4 and
- wherein each of the aforesaid groups being capable to have one or more substituents may optionally be substituted with one or more substituents independently selected from halo, (C1-C4)alkyl, hydroxyl, amino, (C1-C4)alkoxy, or CF3.
A method of treating chronic pain in a subject, comprising administering, to the subject, a pharmaceutically effective amount of a compound represented by the following structure:
- where R1 and R2 are respectively H, (C1-C4)alkyl, (C2-C4)alkenyl, (C1-C4)alkoxy, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl or hydroxyl;
- R3 and R4 are respectively H, (C1-C4)alkyl, keto, (C2-C4)alkenyl, (C1-C4)alkoxy, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl or hydroxyl;
- R5 may be amido, (C1-C4)alkylamido, amido(C1-C4)alkyl;
- carbonyl(C1-C4)alkylamido;
- (C1-C4)alkylcarboxy(C1-C4)alkylamido, or amido(C1-C4)alkylamido;
- and
- R6 is hydroxy (C1-C4)alkylphenyl or a (C5-C13)cyclic or substituted or unsubstituted heterocyclic ring,
- wherein if R4 is keto, x is a single bond, and if R4 is not keto, x is a double bond;
- and m and n are respectively 0-4 and
- wherein each of the aforesaid groups being capable to have one or more substituents may optionally be substituted with one or more substituents independently selected from halo, (C1-C4)alkyl, hydroxyl, amino, (C1-C4)alkoxy, or CF3.
A pharmaceutical composition for treating chronic pain in a subject comprising a compound, in an amount effective at inhibiting long-term hyperexcitability of sensory neurons in a subject to which it is administered, represented by the following structure:
- where R7 and R8 are respectively H, (C1-C4)alkyl, (C2-C4)alkenyl, (C1-C4)alkoxy, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl or keto;
- R9 is amido, (C1-C4)alkylamido, amido(C1-C4)alkyl;
- carbonyl(C1-C4)alkylamido;
- (C1-C4)alkylcarboxy(C1-C4)alkylamido, or amido(C1-C4)alkylamido;
- and
- R10 is carboline, unsubstituted or substituted with one or more substituent selected from (C1-C4)alkyl, hydroxy, (C2-C4)alkenyl, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl and (C1-C4)alkoxy,
- wherein p and q is respectively 0-4;
- and
- wherein each of the aforesaid groups being capable to have one or more substituents may optionally be substituted with one or more substituents independently selected from halo, (C1-C4)alkyl, hydroxyl, amino, (C1-C4)alkoxy, or CF3.
A method of treating chronic pain in a subject, comprising administering, to the subject, a pharmaceutically effective amount of a compound represented by the following structure:
- where R7 and R8 are respectively H, (C1-C4)alkyl, (C2-C4)alkenyl, (C1-C4)alkoxy, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl or keto;
- R9 is amido, (C1-C4)alkylamido, amido(C1-C4)alkyl;
- carbonyl(C1-C4)alkylamido;
- (C1-C4)alkylcarboxy(C1-C4)alkylamido, or amido(C1-C4)alkylamido;
- and
- R10 is carboline, unsubstituted or substituted with one or more substituent selected from (C1-C4)alkyl, hydroxy, (C2-C4)alkenyl, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl and (C1-C4)alkoxy,
- wherein p and q is respectively 0-4;
- and
- wherein each of the aforesaid groups being capable to have one or more substituents may optionally be substituted with one or more substituents independently selected from halo, (C1-C4)alkyl, hydroxyl, amino, (C1-C4)alkoxy, or CF3.
A pharmaceutical composition for treating chronic pain in a subject comprising a compound, in an amount effective at inhibiting long-term hyperexcitability of sensory neurons in a subject to which it is administered, represented by the following structure:
- where R11 is a oxadiazole or triazole, unsubstituted or substituted with (C1-C4)alkyl, hydroxy, (C2-C4)alkenyl, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl, and (C1-C4)alkoxy;
- R12 is a naphthyl, anthryl, phenanthryl, or quinolyl, unsubstituted or substituted with (C1-C4)alkyl, hydroxy, (C2-C4)alkenyl, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl, and (C1-C4)alkoxy;
- and a is H, (C1-C4)alkyl, halo, (C1-C4)alkoxy or hydroxy,
- wherein each of the aforesaid groups being capable to have one or more substituents may optionally be substituted with one or more substituents independently selected from halo, (C1-C4)alkyl, hydroxyl, amino, (C1-C4)alkoxy, or CF3.
A method of treating chronic pain in a subject, comprising administering, to the subject, a pharmaceutically effective amount of a compound represented by the following structure:
- where R11 is a oxadiazole or triazole, unsubstituted or substituted with (C1-C4)alkyl, hydroxy, (C2-C4)alkenyl, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl, and (C1-C4)alkoxy;
- R12 is a naphthyl, anthryl, phenanthryl, or quinolyl, unsubstituted or substituted with (C1-C4)alkyl, hydroxy, (C2-C4)alkenyl, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl, and (C1-C4)alkoxy;
- and α is H, (C1-C4)alkyl, halo, (C1-C4)alkoxy or hydroxy,
- wherein each of the aforesaid groups being capable to have one or more substituents may optionally be substituted with one or more substituents independently selected from halo, (C1-C4)alkyl, hydroxyl, amino, (C1-C4)alkoxy, or CF3.
A pharmaceutical composition for treating chronic pain in a subject comprising a compound, in an amount effective at inhibiting long-term hyperexcitability of sensory neurons in a subject to which it is administered, represented by the following structure:
- wherein R13 may be substituted or unsubstituted phenyl, indolinyl, or isoindolinyl, wherein the substituent may be (C1-C4)alkyl, hydroxy, (C2-C4)alkenyl, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl, and (C1-C4)alkoxy, and wherein more than one (e.g. 2 or 3) such substituents may be present;
- wherein t may be 0-4;
- wherein R14 may be (C1-C4)alkyl, hydroxy, (C2-C4)alkenyl, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl, and (C1-C4)alkoxy;
- wherein R15 and/or R16 may be hydrogen, hydroxyl, (C1-C4)alkyl, (C1-C4)alkoxy, heteroaryl or heterocyclic aryl, or keto or substituted or unsubstituted phenyl, dimethoxyphenyl, or substituted or unsubstituted ethylenedioxyphenyl;
- and
- wherein each of the aforesaid groups being capable to have one or more substituents may optionally be substituted with one or more substituents independently selected from halo, (C1-C4)alkyl, hydroxyl, amino, (C1-C4)alkoxy, or CF3.
A method of treating chronic pain in a subject, comprising administering, to the subject, a pharmaceutically effective amount of a compound represented by the following structure:
- wherein R13 may be substituted or unsubstituted phenyl, indolinyl, or isoindolinyl, wherein the substituent may be (C1-C4)alkyl, hydroxy, (C2-C4)alkenyl, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl, and (C1-C4)alkoxy, and wherein more than one (e.g. 2 or 3) such substituents may be present;
- wherein t may be 0-4;
- wherein R14 may be (C1-C4)alkyl, hydroxy, (C2-C4)alkenyl, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl, and (C1-C4)alkoxy;
- wherein R15 and/or R16 may be hydrogen, hydroxyl, (C1-C4)alkyl, (C1-C4)alkoxy, heteroaryl or heterocyclic aryl, or keto or substituted or unsubstituted phenyl, dimethoxyphenyl, or substituted or unsubstituted ethylenedioxyphenyl;
- and
- wherein each of the aforesaid groups being capable to have one or more substituents may optionally be substituted with one or more substituents independently selected from halo, (C1-C4)alkyl, hydroxyl, amino, (C1-C4)alkoxy, or CF3.
A pharmaceutical composition for treating chronic pain in a subject for treating chronic pain in a subject comprising a compound, in an amount effective at inhibiting long-term hyperexcitability of sensory neurons in a subject to which it is administered, represented by the following structure:
- where Z represents one of the following groups:
- Z=—O— —CH2O— —OCH2— —CH2CH2O— —OCH2CH2— —CH2OCH2— —N— —CH2N— —NCH2— —CH2CH2N— —NCH2CH2— —CH2NCH2—CH2— —CH2CH2— —CH2CH2CH2;
- X represents one of the following functional groups:
- Y represents one of the following functional groups:
- R17 may be aryl, heteroaryl, or heterocyclic aryl, unsubstituted or substituted with one or more of hydroxyl, —CN, (—NO2), (C1-C4)alkoxy, alkoxylalkoxy, halo, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)alkyl, or —SO3H;
- R18 is one of the following functional group:
- R19 is aryl or heteroaryl, un-substituted or substituted by one or more lower-alkyl, lower-alkoxy, hydroxy, alkoxy, amino, alkylamino or halogen groups, or (C1-C5)alkyl;
- and
- R17 may be aryl, heteroaryl, or heterocyclic aryl, unsubstituted or substituted with one or more of hydroxyl, —CN, (—NO2), (C1-C4)alkoxy, alkoxylalkoxy, halo, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)alkyl, or —SO3H
A method of treating chronic pain in a subject, comprising administering, to the subject, a pharmaceutically effective amount of a compound represented by the following structure:
- where Z represents one of the following groups:
- Z=—O— —CH2O— —OCH2— —CH2CH2O— —OCH2CH2— —CH2OCH2— —N— —CH2N— —NCH2— —CH2CH2N— —NCH2CH2— —CH2NCH2—CH2— —CH2CH2— —CH2CH2CH2;
- X represents one of the following functional groups:
- Y represents one of the following functional groups:
- R17 may be aryl, heteroaryl, or heterocyclic aryl, unsubstituted or substituted with one or more of hydroxyl, —CN, (—NO2), (C1-C4)alkoxy, alkoxylalkoxy, halo, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)alkyl, or —SO3H;
- R18 is one of the following functional group:
- R19 is aryl or heteroaryl, un-substituted or substituted by one or more lower-alkyl, lower-alkoxy, hydroxy, alkoxy, amino, alkylamino or halogen groups, or (C1-C5)alkyl;
- and
- R17 may be aryl, heteroaryl, or heterocyclic aryl, unsubstituted or substituted with one or more of hydroxyl, —CN, (—NO2), (C1-C4)alkoxy, alkoxylalkoxy, halo, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)alkyl, or —SO3H.
A pharmaceutical composition for treating chronic pain in a subject comprising a compound, in an amount effective at inhibiting long-term hyperexcitability of sensory neurons in a subject to which it is administered, represented by the following structure:
- Ar1—X—Ar2
- where X* is one of the following groups;
- Ar1 and Ar2 are respectively aryl or heteroaryl, substituted or unsubstituted,
- wherein the substituent(s) of any of the foregoing groups, which are optionally present and may be singular or plural, is selected from (C1-C4)alkyl, aryl, alkylaryl, (C1-C4)alkoxy, (C1-C4)alkylcarbonyl, halo, alkenyl (e.g., (C2-C4)alkenyl), alkynyl (e.g., (C2-C4)alkynyl) and hydroxy;
- and Rx is hydrogen, halo, (C1-C4)alkoxy or (C1-C4)alkyl;
- and
- wherein each of the aforesaid groups being capable to have one or more substituents may optionally be substituted with one or more substituents independently selected from halo, (C1-C4)alkyl, hydroxyl, amino, (C1-C4)alkoxy, or CF3.
A method of treating chronic pain in a subject, comprising administering, to the subject, a pharmaceutically effective amount of a compound represented by the following structure:
- Ar1—X*—Ar2
- where X* is one of the following groups;
- Ar1 and Ar2 are respectively aryl or heteroaryl, substituted or unsubstituted,
- wherein the substituent(s) of any of the foregoing groups, which are optionally present and may be singular or plural, is selected from (C1-C4)alkyl, aryl, alkylaryl, (C1-C4)alkoxy, (C1-C4)alkylcarbonyl, halo, alkenyl (e.g., (C2-C4)alkenyl), alkynyl (e.g., (C2-C4)alkynyl) and hydroxy;
- and Rx is hydrogen, halo, (C1-C4)alkoxy or (C1-C4)alkyl;
- and
- wherein each of the aforesaid groups being capable to have one or more substituents may optionally be substituted with one or more substituents independently selected from halo, (C1-C4)alkyl, hydroxyl, amino, (C1-C4)alkoxy, or CF3.
A pharmaceutical composition for treating chronic pain in a subject comprising a compound, in an amount effective at inhibiting long-term hyperexcitability of sensory neurons in a subject to which it is administered, represented by the following structure:
- Ar1*—X**—Ar2*
- where X** is one of the following groups:
- wherein n is 1-4;
- wherein Ar1* is a substituted or unsubstituted group;
- wherein Ar2* is a substituted or unsubstituted aryl or heteroaryl,
- wherein G is H, (C1-C4)alkyl, hydroxy, (C2-C4)alkenyl, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl, and (C1-C4)alkoxy;
- X is O, N, or S;
- R21 and R22 are respectively H, alkyl (e.g., (C1-C4)alkyl), aryl, (C1-C4)alkoxy, (C1-C4)alkylcarbonyl, phenyl, alkylphenyl, (C2-C4)alkenyl, (C2-C4)alkynyl, halo or hydroxy;
- each of the aforesaid groups optionally having one or more substituents selected from the group consisting of halo, (C1-C4)alkyl, hydroxyl, amino, (C1-C4)alkoxy, and CF3.
A method of treating chronic pain in a subject, comprising administering, to the subject, a pharmaceutically effective amount of a compound represented by the following structure:
- Ar1*X**—Ar2*
- where X** is one of the following groups:
- wherein n is 1-4;
- wherein Ar1* is a substituted or unsubstituted group;
- wherein Ar2* is a substituted or unsubstituted aryl or heteroaryl,
- wherein G is H, (C1-C4)alkyl, hydroxy, (C2-C4)alkenyl, (C2-C4)alkynyl, halo, carbamoyl, amido, amino, cyano, (C1-C4)alkylcarbonyl, and (C1-C4)alkoxy;
- X is O, N, or S;
- R21 and R22 are respectively H, alkyl (e.g., (C1-C4)alkyl), aryl, (C1-C4)alkoxy, (C1-C4)alkylcarbonyl, phenyl, alkylphenyl, (C2-C4)alkenyl, (C2-C4)alkynyl, halo or hydroxy;
- each of the aforesaid groups optionally have one or more substituents selected from the group consisting of halo, (C1-C4)alkyl, hydroxyl, amino, (C1-C4)alkoxy, and CF3.
A pharmaceutical composition comprising a compound, in an amount effective at inhibiting long-term hyperexcitability of sensory neurons in a subject to which it is administered, represented by
A method of treating chronic pain in a subject, comprising administering, to the subject, a pharmaceutically effective amount of a compound represented by the following structure:
A pharmaceutical composition comprising a compound, in an amount effective at inhibiting long-term hyperexcitability of sensory neurons in a subject to which it is administered, represented by
A method of treating chronic pain in a subject, comprising administering, to the subject, a pharmaceutically effective amount of a compound represented by the following structure:
A pharmaceutical composition comprising a compound having Formula XI:
- where R1 is F, COOH, Cl, or I, hydrogen, lower alkyl, aryl, alkylamino, arylamino, aryloxy or alkoxy;
- R2 is CH3O, CH3CH2O, (C1-C4)alkoxy, or hydroxyl, hydrogen, lower alkyl, aryl, alkylamino, arylamino, aryloxy or alkoxy;
- R3 is a halogen, alkyl, aryl, cycloalkyl;
- alkoxy, cycloalkoxy, allyl-O, aryl-O, NCO—R′, NSO2R′, CO—R′, CH3OCH2O, CH3CO, CH3COO, CH2OCH, O(CH2)2CH3, hydrogen, lower, alkylamino, arylamino, aryloxy, COOH, COOR′, or CONR′1R′2, wherein R′ is (C1-C4)alkyl;
- R4 and R5 are respectively H, OH, CH3O, (C1-C4)alkoxy, lower alkyl, aryl, alkylamino, arylamino, aryloxy or alkoxy;
- X is Oxygen or Nitrogen;
- and
- Y is Nitrogen or Carbon.
A method of treating chronic pain in a subject, comprising administering, to the subject, a pharmaceutically effective amount of a compound represented by the following structure:
- where R1 is fluoro, COOH, chloro, or iodo, hydrogen, lower alkyl, aryl, alkylamino, arylamino, aryloxy or alkoxy;
- R2 is CH3O, CH3CH2O, (C1-C4)alkoxy, or hydroxyl, hydrogen, lower alkyl, aryl, alkylamino, arlamino, aryloxy or alkoxy;
- R3 is a halogen, alkyl, aryl, cycloalkyl;
- alkoxy, cycloalkoxy, allyl-O, aryl-O, NCO—R′, NSO2R′, CO—R′, CH3OCH2O, CH3CO, CH3COO, CH2OCH, O(CH2)2CH3, hydrogen, lower, alkylamino, arylamino, aryloxy, COOH, COOR′, or CONR′1R′2, wherein R′ is (C1-C4)alkyl;
- R4 and R5 are respectively H, OH, CH3O, (C1-C4)alkoxy, lower alkyl, aryl, alkylamino, arylamino, aryloxy or alkoxy;
- X is Oxygen or Nitrogen;
- and
- Y is Nitrogen or Carbon.
Dependencies are inferred from the claim text.